6-O-methylerythromycin A (clarithromycin), shown below, is a potent macrolide antibiotic disclosed in U.S. Pat. No. 4,331,803. ##STR1##
In general, the process for making clarithromycin can be thought of as a four-step procedure beginning with erythromycin A as the starting material:
Step 1: optionally convert the 9-oxo group to an oxime; PA1 Step 2: protect the 2' and 4" hydroxyl groups; PA1 Step 3: methylate the 6-hydroxyl group; and PA1 Step 4: deprotect at the 2', 4" and 9-positions. PA1 R.sub.2 and R.sub.4 are independently a hydrogen or a hydroxy-protecting group; PA1 R.sub.3 is a loweralkyl or aryl group; PA1 R.sub.5 is a hydrogen, hydroxy or a protected hydroxy group; and PA1 R.sub.6 and R.sub.7 are independently at each occurrence a hydrogen, an alkyl or an aryl group. PA1 a) reacting an erythromycin of the formula I: ##STR3## wherein R.sub.5 is as defined above, with hydrazine to convert the 9-keto into a corresponding 9-hydrazone erythromycin; PA1 b) protecting the 2'-hydroxy, and optionally protecting the 4"-hydroxy, and the amino nitrogen of the hydrazone with hydroxy and nitrogen protecting groups, respectively; and PA1 c) selectively alkylating the 6-hydroxy group. PA1 a) reacting an erythromycin of the formula III: ##STR4## wherein R.sub.5 is as defined above, with hydrazine to convert the 9-keto into a corresponding 9-hydrazone erythromycin; PA1 b) reacting the hydrazone from step (a) with a ketone, an aldehyde or an acetal thereof or an ortho formate to produce a corresponding erythromycin 9-azine; PA1 c) protecting the 2'-hydroxy and optionally protecting the 4"-hydroxy and the amino nitrogen of the 9-azine, with hydroxy-protecting and nitrogen-protecting groups, respectively; and PA1 d) selectively alkylating the 6-hydroxy group. PA1 R.sub.2 and R.sub.4 are independently a hydrogen or a hydroxy-protecting group; PA1 R.sub.3 is a loweralkyl or an aryl group; PA1 R.sub.5 is a hydrogen, hydroxy or a protected hydroxy group; and PA1 R.sub.6 and R.sub.7 are independently at each occurrence a hydrogen, an alkyl or an aryl group. PA1 wherein R.sub.2 and R.sub.4 are trimethylsilyl groups, R.sub.5 is hydroxyl, R.sub.3 is methyl and R and R.sub.1 are independently hydrogen and isopropylidene; and
A variety of means for preparing 6-O-methylerythromycin A have been described. 6-O-methylerythromycin A can be prepared by methylating a 2'-O-3'-N-dibenzyloxycarbonyl-des-N-methyl derivative of erythromycin A (U.S. Pat. No. 4,331,803). 6-O-methylerythromycin A can also be made from 9-oxime erythromycin A derivatives (See, e.g., U.S. Pat. Nos. 5,274,085; 4,680,386; 4,668,776; 4,670,549 and 4,672,109, U.S. Pat. No. 4,990,602 and European Patent Application 0260938 A2).
In those reports relating to 9-oxime erythromycin A derivatives, the oxime is protected during methylation with a 2-alkenyl group (U.S. Pat. Nos. 4,670,549 and 4,668,776), a benzyl or substituted benzyl group (U.S. Pat. Nos. 4,680,386, and 4,670,549) or a moiety selected from the group consisting of lower alkyl, substituted alkyl, lower alkenyl, aryl substituted methyl, substituted oxalkyl, substituted thiomethyl (U.S. Pat. No. 4,672,109), and ketal group (U.S. Pat. No. 4,990,602).
There continues to be a need to provide a rapid, efficient method of producing 6-O-alkyl erythromycin compounds that uses mild, neutral synthetic conditions and to provide novel intermediates useful in the production of 6-O-alkyl erythromycin derivatives.